The glutamate decarboxylase 2 (GAD2) antibody targets the 65 kDa isoform of GAD, an enzyme critical for synthesizing gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. GAD exists as two isoforms, GAD65 (encoded by GAD2) and GAD67 (GAD1), with distinct cellular roles and tissue distributions. While GAD67 is constitutively active, GAD65 is transiently activated in response to metabolic demands. GAD65 is expressed in pancreatic β-cells and neurons, where it contributes to GABA production and insulin secretion regulation.
GAD2 autoantibodies are hallmark biomarkers in autoimmune disorders, notably type 1 diabetes mellitus (T1DM), where they indicate immune-mediated destruction of pancreatic β-cells. Their presence often precedes clinical symptoms, aiding early diagnosis and risk stratification. Additionally, these antibodies are linked to rare neurological conditions like stiff-person syndrome (SPS) and cerebellar ataxia, reflecting cross-reactivity with neuronal GAD65. The exact pathogenic mechanism remains debated, though antibody-mediated interference with GABAergic signaling or enzyme function is hypothesized.
Detection methods (e.g., immunoassays, cell-based tests) are vital for diagnosing and monitoring these conditions. While GAD2 antibodies are predominantly associated with T1DM, their coexistence with other autoantibodies (e.g., IA-2. ZnT8) enhances diagnostic specificity. Research continues to explore their role in disease progression and potential therapeutic targets.